Any drug substance or drug product has to maintain the same quality, safety and efficacy throughout the lifecycle of a product. Generally, the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light.
As we understood the quality of substance or product is varying in the presence of temperature and humidity over the period of time, any sponsor/applicant needs to provide supporting data and information on stability of a concerned product for the registration/application. Based on the generated data the appropriate storage conditions along with the re-test period for the drug substance or a shelf-life for the drug product can be established.
The temperature and climate of the world has been classified in to different zones based on the temperature and humidity.
Lets understand what kind of stability data package is required to support the marketing application.
To evaluate the behaviour of the molecule, one has to perform stress testing to identify the likely degradation products, what are the degradation pathways and intrinsic stability of the molecule. It also helps to validate the stability indicating power of the analytical method used to identify the degradation products.
The stress testing can be conducted on a single batch of drug substance including the effect of temperature (in 10°C increments above that for accelerated testing); humidity; oxidation; hydrolysis and photolysis on the drug substance.
The formal stability studies for the drug product should be designed based on the behaviour and properties and stability of the drug substance.
What are the different types of stability data to be presented in any registration package for the health authority review?
The below stability data to be included in the dossier as part of the initial applications.
- Formal Stability Study
- Photo-stability Study
- Thermal cycling/Freeze-Thaw study
- In-use stability Study
Formal Stability Study:
Based on the stress data and storage conditions of drug substance and drug product the stability to be evaluated at different conditions to test thermal stability and sensitivity to moisture.
Substances/Products to be stored at Room Temperature:
Substances/Products to be stored in Refrigerator:
Substances/Products to be stored in a Freezer:
The material of the container closure system used to pack the drug substance/drug product also plays a crucial role in the selection of the stability conditions. The substance/products that are required to store in a semi-permeable containers have different stability requirements as presented below.
Substances/Products to be packaged in semi-permeable containers:
Substances/Products intended for storage below -20°C
Drug substances/products intended for storage below -20°C should be treated on a case-by-case basis.
So far we understood the requirements of stability conditions in which data to be presented.
Let us now dive into further details on what are the minimum expectations on testing frequency, number of batches to be tested, in which packaging conditions etc.,
Testing Frequency:
Frequency is nothing but how many times the drug substance or drug product to be testing under the specified storage conditions. The main idea is the frequency should be well designed and sufficient to establish the stability profile.
As we know there are 03 storage conditions, long-term, intermediate and accelerated.
Accelerated Conditions – The minimum data expected in the accelerated condition is 6-months and a minimum of 03 time points to be tested including initial and final time points.
Hence, it can be concluded that for accelerated storage condition 0, 3 and 6 are the frequency (time points) required.
In any case if increased testing needs to be generated, it can be conducted either by adding samples at the final time point or by including a fourth time point in the study design.
Intermediate Conditions – The minimum data expected in the intermediate condition is 6-months and a minimum of 03 time points to be tested including initial and final time points.
Hence, it can be concluded that for intermediate storage condition 0, 3 and 6 are the frequency (time points) required.
Long-term Conditions – The minimum data expected in the long-term condition is 12-months and this data is considered as a real time and accrued data to be generated and submitted till the claimed re-test period or shelf life of a product.
The frequency of long-term storage condition includes every 3-months in the first year, 6-months in second year and yearly once thereafter.
Hence, it can be concluded that for long-term storage condition 0, 3, 6, 9, 12, 18, 24, 36, 48 and 60 are the frequency (time points) required.
We understood what are the stability conditions and testing frequency, now let us explore further requirements.
What is the agency expectation on number of batches?
The accelerated, intermediate and long-term data on at least three pilot scale batches to be included in the initial application.
For Drug Substances:
All the three batches to be manufactured to a minimum of pilot scale using the same synthetic route, method of manufacture and the procedure that simulated the final process to be used for production of the batches.
For Drug Products:
The primary/pilot batches should be of the same formulation and packaged in the same container closure system.
An exception is that two of the three batches should be at least on pilot scale batches and the third one can be smaller, if justified.
What is the agency expectation on packaging requirements of the stability batches?
The stability studies should be conducted on the drug substance/drug product packaged in a container closure system that is the same as or simulates the packaging proposed for storage, distribution and marketing during commercialization.
How the labelling of the drug substance/drug product is impacted?
The purpose is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances.
The statement should be based on the stability evaluation of the drug substance/drug product. An expiration date should be displayed on the outer label.
What parameters to be tested during the stability study?
In general the stability studies should include testing of the attributes that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. (Physical, chemical, biological, and microbiological attributes).
Now we need to understand the attributes to be tested depends on the material and specific to the dosage form.
For an Drug Substance/Active Pharmaceutical Ingredient
Description/Appearance, Identification, Assay, Impurities, polymorphic form, water content and microbial limits.
For a Drug Product
Description/Appearance, Identification, Assay, Degradation products, water content and microbial limits.
Dosage Form Specific Attributes
Oral Solid Dosage Form (Tablets)
Appearance, friability, hardness, colour, odour, moisture, strength, and dissolution.
Oral Solid Dosage Form (Capsules)
Strength, moisture, colour, appearance, shape, brittleness, dissolution
Emulsions:
Colour, odour, pH, viscosity, and strength
Oral Solutions:
Appearance (precipitate, cloudiness), strength, pH, color, odor, redispersibility, dissolution (suspensions), and clarity (solutions).
Oral Powders:
Appearance, strength, color, odor, and moisture
Topicals & Ophthalmics:
Appearance, clarity, color, homogenecity, odor, pH, re-suspendibility (lotions), consistency, particle size distribution, strength, and weight loss (plastic containers).
Parenterals (SVP):
Strength, appearance, color, particulate matter, pH, sterility, and pyrogenicity (at reasonable intervals)
Parenterals (LVP):
Strength, appearance, color, particulate matter, pH, sterility, and pyrogenicity (at reasonable intervals)
Drug products packaged in semi-permeable containers
As discussed above, the products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability.
Note: Any differences between the release and shelf life acceptance criteria for anti-microbial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation.
Photo stability testing
Photo stability testing is carried out to demonstrate effect of light exposure on the stability of pharmaceuticals that result in acceptable change.
The light source that will produce a output similar to D65/ID65 emission standard, that composed of UV and visible light to maintain an appropriate control of temperature to minimize the effect of temperature changes or include a dark control in the same environment.
A near UV fluorescent lamp with a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm can be used as an alternative light source.
Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter. protected samples can be used as dark controls to evaluate the contribution of thermally induced change to the total observed change.
The testing is carried out on a SINGLE batch, and approach includes test on drug substance, drug product outside immediate pack, drug product in immediate pack, and drug product in marketing pack.
Photo stability testing includes two parts, Forced degradation testing and Confirmatory testing
FDT used to evaluate the photosensitivity of the material for method development and/or degradation pathway elucidation, useful in developing and validating suitable analytical methods.
Confirmatory studies provide the information necessary for handling, packaging, and labelling.
All suitable precautions should be taken to provide minimal interference with the exposure of samples under test.
The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies.
The confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product.
At the end of the exposure period, the samples should be examined for any changes in physical properties.
Thermal cycling/Freeze-Thaw study
A thermal cycling or freeze-thaw study is the one performed to address the excursions during the transportation.
A thermal cycling study is done to determine the impact of temperature excursions outside the product’s labelled storage conditions. It is simulated below and above the product’s labelled storage conditions for multiple cycles, and the impact on the product quality will be evaluated.
We need to understand the difference between the thermal cycling and temperature excursion, a thermal-cycling study is performed by simulating upper and lower side excursion multiple times whereas, the temperature excursion study, is the one-sided excursion without cycling.
The idea or rationale behind performing the thermal excursion study is, usually the drug products are stored in the controlled environment during the manufacturing and storage however, these are needed to be transported to different area for marketing where the conditions can not be predictive and extreme challenges to be anticipated than the stability conditions discussed above in the formal stability studies (long-term, intermediate and accelerated). This gives an indication how a product will behave to adverse conditions during transportation.
The protocol to be designed considering the various factors such as the product development data, route of transportation, possible extreme conditions, and product strengths.
Let’s consider a product that have a recommended labelled storage conditions are at 20°C to 25°C, then the samples are place on stability chamber at -20°C for 48 hours and then moved to a stability chamber at 40°C/ 75% RH for 48 hours. The process is repeated for 3 cycles.
The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in-use shelf life.
In-use stability Study
The purpose of in-use stability testing is to establish the time period during which any multi dose product remains in its quality with in an acceptable range once the container is opened.
Let’s consider a bottle of 30 units to be taken over a period a month, we need to understand that due to the repeated opening and closing of the container during the medicine intake, it may pose a risk to its active content that may have impact on physical form, chemical composition, microbial contamination.
Any marketing application should include in-use stability data on their multi-dose product or else a justification to be provided which is to be based on the experimental results.
How many batches data to be submitted?
Based on the EU recommendations a minimum of two batches, at least pilot scale batches, data should be presented in the dossier. At least one of the batches should be chosen towards the end of its shelf life.
The test to be designed to simulate the use od the product in regular practice taking into consideration the fill volume of the container and any dilution/reconstitution before use.
The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in-use shelf life.
What Parameters to be tested?
The appropriate physical, chemical and microbial properties of the product susceptible to change during use should be monitored. The tests used must be appropriate to individual dosage forms.
What is a Significant Change? What is its role in defining the quality of product?
The drug substance/drug product when tested under certain storage conditions its acceptance to certain limits determine whether the materials is meeting the quality requirements or not.
The Significant change can be defined as any failure to meet its specification.
For drug product is more elaborated specific to parameters.
- A 5% change in assay from its initial value;
- Any degradation product’s exceeding its acceptance criterion;
- Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test;
- Failure to meet the acceptance criterion for pH; or
- Failure to meet the acceptance criteria for dissolution for 12 dosage units.
For products stored in a semi-permeable container a 5% loss in water from its initial value is considered a significant change.
How to deal if a significant change occurs?
If a significant change occurs at any time during 6-months testing at the accelerated storage condition, additional testing of the intermediate storage condition should be conducted and evaluated against significant change criteria.
The data on 3 batches at intermediate storage conditions to be included as a part of submission though the significant change occurred in any of the one batch of accelerated condition.
If significant change occurs
- Within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided.
- Between 3 and 6 months’ testing at the accelerated storage condition, the proposed re-test period should be based on the real time data.
What is a Stability Commitment and whom to provide in the application?
A commitment on stability testing from the applicant as well as the manufacturer to be included as part of the dossier.
Based on the stability data available/submitted in the dossier the applicant/manufacturer should include one of the below statements as part of the commitment.
- If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period/shelf-life.
- If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re- test period.
- If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period.